Nausea Vomiting in Pregnancy

Clinical Knowledge Summaries: Previous version – Nausea and vomiting in pregnancy

This PRODIGY guidance topic is obsolete and has been replaced by a CKS Topic Review.

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Nausea and vomiting in pregnancy This PRODIGY guidance topic is obsolete and has been replaced by a CKS Topic Review.


About this topic Have I got the right topic? Age from 12 to 60 years

This guidance covers the management of nausea and vomiting in pregnancy in primary care.

This guidance does not cover other causes of nausea and vomiting (obstetric and non-obstetric) or dyspepsia during pregnancy.

There are separate CKS topics on Dyspepsia — pregnancy-associated, Hypertension in pregnancy, Hyperthyroidism, and Gastroenteritis.

The target audience for this guidance is healthcare professionals working within the NHS in England, and providing first contact or primary health care. Patient information from NHS Direct is intended to be printed and given to people with this condition, and the Shared decision making sections are designed to provide a focus for discussion during the consultation about the treatment options.

Changes Version 1.0.0, revision planned in 2008. Last revised in July 2005

October 2005 — minor technical update. Issued in November 2005.

Previous changes March 2005 — reviewed. Validated in June 2005 and issued in July 2005.

December 2001 — reviewed. Validated in March 2002 and issued in April 2002.

January 1999 — written, replacing the guidance on Hyperemesis of pregnancy. Validated in March 1999 and issued in August 1999.

Update New evidence Evidence-based guidelines

No new evidence-based guidelines since 1 March 2007.

HTAs (Health Technology Assessments)

No new HTAs since 1 March 2007.

Economic appraisals

No new economic appraisals relevant to England since 1 March 2007.

Systematic reviews and meta-analyses

No new systematic review or meta-analysis since 1 March 2007.

Primary evidence

No new high quality randomized controlled trials since 1 March 2007.

New policies No new national policies or guidelines since 1 March 2007.

New safety alerts No new safety alerts since 1 March 2007.

Changes in product availability No changes in product availability since 1 March 2007.

Concise knowledge for clinical scenarios Which therapy? • Reassure:

o Nausea and vomiting is a normal part of pregnancy. o Symptoms are most common and troublesome in early pregnancy, and resolve in most

women by 16 weeks.




• Offer dietary and lifestyle advice: o Eat small, frequent meals, high in carbohydrate and low in fat. o Eat plain (or ginger) biscuits about 20 minutes before getting up. o Drinking little and often rather than large amounts may help to prevent vomiting. o Avoid food and smells that trigger symptoms. o Try to get plenty of rest as tiredness can make nausea worse.

• Drug treatment is indicated if symptoms are persistent, severe and prevent daily activities. Note: no drug is licensed for the treatment of nausea and vomiting in pregnancy. o Promethazine is recommended first-line treatment:

▪ Promethazine hydrochloride is available in two strengths (10 mg and 25 mg) and allows dosing flexibility.

▪ Promethazine teoclate is only available as a 25 mg tablet. o Cyclizine is an alternative first-line treatment. o Regular doses to achieve adequate blood concentrations of the drug may be helpful.

Practical prescribing points For further information please see the Medicines Compendium (www.medicines.org.uk) or the British National Formulary (www.bnf.org). For more information about the use of drugs in pregnancy, contact the National Teratology Information Service (tel: 0191 232 1525).

Adverse effects • Both promethazine and cyclizine cause drowsiness. The degree of sedation will vary

between individuals and will depend on the dose given. Anticholinergic adverse effects may also occur (e.g. blurred vision and dry mouth).

Cautions in pregnancy • No drug is licensed for the treatment of nausea and vomiting in pregnancy. • There is no convincing evidence to suggest that therapeutic doses of promethazine and

cyclizine are associated with an increased risk of congenital abnormalities above the background rate for the population.

• Promethazine may interfere with pregnancy testing (urine) to produce false-positive and false-negative results.

• Promethazine should be discontinued at least 2 weeks before delivery because of the risk of irritability and excitement in the neonate.

Should I refer or investigate? Refer? • Urgent admission is necessary for intravenous fluid, electrolyte and vitamin

replacement if the following are suspected: o Dehydration o Acidosis secondary to ketosis o Electrolyte imbalance o Nutritional deficiency o Any suspicion of Wernicke's encephalopathy o Severe, uncontrolled symptoms leading to concern about the well-being of mother or

fetus

Investigate? • Investigations are only indicated where there is concern regarding risk to the health of

the mother or fetus or both. • In severe cases:

o Urea and electrolytes and calcium may reveal dehydration, renal impairment, and metabolic disturbances (e.g. acidosis).

o Liver function tests may be abnormal. o Urinalysis may show marked ketonuria. o Thyroid function tests may reveal a high free thyroxine (T4) level or low thyroid-

stimulating hormone (TSH) level, or both. High free tri-iodothyronine (T3) is much less common.

Prescriptions Advice only: nausea and vomiting in pregnancy • Age from 12 to 60 years




• Advice: Eating small but frequent meals. Foods high in carbohydrate are best such as bread, crackers, etc. Eating a plain (or ginger) biscuit about 20 minutes before getting up is said by some women to help. Have lots to drink to avoid dehydration. Drinking little and often rather than large amounts may help to prevent vomiting. Avoid triggers. (Some women find a 'trigger' sets off their sickness such as a particular smell or stress.)

Promethazine hydrochloride 10mg to 20mg at night Age from 12 to 60 years

• Promethazine hydrochloride 10mg tablets. Take one to two tablets at night to prevent sickness. (The dose may be repeated the next morning if necessary.) Supply 56 tablets.

• NHS Cost £1.71 • Licensed use: no • Patient Information: Take a maximum of two tablets at night. This dose may be repeated

the next morning if needed, but it may make you feel drowsy.

Promethazine hydrochloride 25mg at night Age from 12 to 60 years

• Promethazine hydrochloride 25mg tablets. Take one tablet at night to prevent sickness. (The dose may be repeated the next morning if necessary.) Supply 56 tablets.

• NHS Cost £2.55 • Licensed use: no • Patient Information: Do not take more than one tablet at night. This dose may be repeated

the next morning if needed, but it may make you feel drowsy.

Promethazine teoclate 25mg at night Age from 12 to 60 years

• Promethazine teoclate 25mg tablets. Take one tablet at night to prevent sickness. (The dose may be repeated the next morning if necessary.) Supply 56 tablets.

• NHS Cost £6.26 • Licensed use: no • Patient Information: Do not take more than one tablet at night. This dose may be increased

further to a maximum of 4 tablets in 24 hours if necessary.

Cyclizine 50mg up to three times a day Age from 12 to 60 years

• Cyclizine 50mg tablets. Take one tablet up to three times a day, to prevent sickness. Supply 56 tablets.

• NHS Cost £3.45 • Licensed use: no

Drug rationale Drugs not included • Prochlorperazine and metoclopramide are recommended as second-line treatment.

There are fewer studies on these drugs than on promethazine and cyclizine. Extrapyramidal reactions sometimes occur, particularly in young women [NTIS, 1999b; NTIS, 1999c].

• Antihistamine anti-emetics other than promethazine and cyclizine have not been studied extensively in human pregnancy and their long-term safety record is less clear.

• Pyridoxine (vitamin B6) may reduce the severity of nausea but has no significant effect on vomiting [Sahakian et al, 1991; Vutyavanich et al, 1995]. It is not offered because of uncertainty about its effectiveness and the optimal dose. Pyridoxine, however, is less likely to cause adverse effects than antihistamine anti-emetics [Jewell and Young, 2003].

Drugs included Note: no drug is licensed for the treatment of nausea and vomiting in pregnancy.

• Promethazine is the preferred first-line treatment if drug therapy is necessary [NTIS, 2002]. It is available as the hydrochloride or teoclate salt. The hydrochloride salt is offered as a regular night-time dose. It is available as 10 mg tablets, which can be titrated for optimum effect. Up to 25 mg can be taken as one dose, and this can be repeated in the morning if necessary. Promethazine teoclate is only available as a 25 mg tablet, which restricts dosing flexibility.

• Cyclizine is also offered as an alternative first-line treatment [NTIS, 1999a].

Shared decision making




• About 3 in 4 pregnant women feel sick or vomit during early pregnancy. Symptoms go by week 16 in most cases.

• Vomiting does not affect your baby unless you become very ill (which is rare). • No treatment is needed in most cases. Things that may help include:

o Eating small but frequent meals. Foods high in carbohydrate are best such as bread, crackers, and so on. Eating a plain (or ginger) biscuit about 20 minutes before getting up is said by some women to help.

o Having lots to drink to avoid dehydration. Drinking little and often rather than large amounts may help to prevent vomiting.

o Avoiding triggers. (Some women find a 'trigger', such as a particular smell or stress, sets off their sickness.)

• Anti-sickness medication such as promethazine or cyclizine is an option if symptoms are severe or not settling. Many women have used these medicines, and there is no evidence that they harm a developing baby.

Detailed knowledge about this topic Goals and outcome measures Goals • To reassure • To reduce nausea and vomiting • To reduce time off work and other lifestyle disruptions caused by symptoms

Background information What is it? • Nausea and vomiting are common symptoms experienced by most women in the early

stages of pregnancy. • Although often referred to as 'morning sickness', nausea and vomiting can occur at

all times of the day. About 2–4% of women experience symptoms only in the morning and 80–95% of women experience symptoms throughout the day.

• A spectrum of severity exists, from mild nausea to rare life-threatening symptoms. o Most cases are regarded as mild, but the effect on pregnant women's sense of well-

being and daily activities has probably been underestimated. o Hyperemesis gravidarum is the most severe form of nausea and vomiting in

pregnancy and is defined as persistent nausea and vomiting leading to dehydration, ketonuria, electrolyte imbalance and weight loss greater than 5% of pre-pregnancy weight.

• The pathophysiology is poorly understood and is likely to be multifactorial. Theories of the cause include: o Hormonal:

▪ Human chorionic gonadotrophin (hCG) levels peak during the first trimester, and are higher in some conditions associated with nausea and vomiting in pregnancy (hydatidiform mole and multiple gestation) [Davis, 2004]. However, no consistent correlation has been found between the severity of nausea and vomiting, and hCG levels.

▪ High oestrogen levels are related to increased incidence of nausea and vomiting in pregnancy [ACOG, 2004; Davis, 2004].

o Gastrointestinal dysmotility results in delayed gastric emptying and lower oesophageal sphincter pressure.

o Autonomic nervous system disturbance is related to the physiological changes in pregnancy in blood volume, temperature, heart rate, and vascular resistance.

o Nutritional deficiency: deficiencies of vitamin B6 have been noted in pregnant women [Czeizel et al, 1992] and vitamin B6 use during pregnancy is associated with some improvement in nausea severity [Jewell and Young, 2003].

o Psychological factors: some women experience ambivalence or rejection of the pregnancy, particularly if the pregnancy is unplanned [Davis, 2004]. Another theory is that pregnant women may be transforming psychological distress into physical symptoms [Buckwalter and Simpson, 2002].

o Hepatic abnormalities: abnormalities of liver function tests are common in women with hyperemesis gravidarum; however, it is possible that these are secondary to the condition.




o Lipid metabolism: a slow adaptation of the liver to the increased levels of hormones in pregnancy may cause hyperemesis gravidarum and result in differences in serum lipid and lipoproteins.

o Helicobacter pylori infection has been found to be significantly associated with hyperemesis gravidarum [Kocak et al, 1999; Shirin et al, 2004]. Five case reports have reported an improvement in symptoms following either erythromycin therapy or a combination of antibiotics and proton pump inhibitor or H2 receptor antagonist [Kuscu and Koyuncu, 2002].

o Hyperthyroxinaemia (high thyroxine levels) may be associated with hyperemesis gravidarum. It is postulated that hCG, which shares a common alpha subunit with thyroid-stimulating hormone, acts as a thyroid stimulator. This usually resolves spontaneously as pregnancy progresses, in parallel with the hyperemesis gravidarum [DTB, 1995].

• Nausea and vomiting in pregnancy may have a functional role. o One theory is that an increased sensitivity to smell is a natural protective measure,

making women more aware of potentially noxious agents in the environment. o Another hypothesis is that maintaining low levels of insulin in the first trimester of

pregnancy is vital to early placental development [Huxley, 2000]. Human chorionic gonadotrophin (hCG) has been shown to activate the thyroid, stimulating the production and release of thyroxine, a stimulator of placental growth. Insulin has been reported to inhibit hCG production in the first trimester and therefore hinder placental growth.

[Kuscu and Koyuncu, 2002; Jewell and Young, 2003; ACOG, 2004; Davis, 2004]

How common is it? • Nausea in pregnancy is reported in 50–80% of pregnant women; 52% of pregnant

women experience symptoms of both nausea and vomiting during early pregnancy, and 28% experience nausea only.

• Hyperemesis gravidarum affects between 0.3% and 2% of all pregnant women. • Increased incidence of nausea and vomiting is associated with:

o Multiple pregnancies o Mother or sister with nausea and vomiting in pregnancy o Previous pregnancy with nausea and vomiting o Hydatidiform mole o Nulliparity o Unplanned pregnancy o Female gender of the fetus o Non-smoking o Low socio-economic status o Younger maternal age o Dependent personality trait o Obesity o Stress

• Reduced incidence is noted in smokers and in women who subsequently experience miscarriage.

• Low body mass index has recently been linked to high incidence of nausea and vomiting in pregnancy in one small observational study of 41 women [Ben Aroya et al, 2005].

[Abell and Riely, 1992; ACOG, 2004; Davis, 2004]

How do I know my patient has it? Clinical features • Symptoms commonly start 4–7 weeks after the last menstrual period and cease by

12 weeks in 60% of affected women. About 9% of affected women have symptoms that persist beyond 16 weeks and may persist until 22 weeks of gestation [Lagiou et al, 2003; Davis, 2004].

• Symptoms are often episodic and can occur at any time during the day [Gadsby et al, 1993].

• Typical symptoms include nausea, vomiting, fatigue, anorexia and weight loss (<5% of pre-pregnancy bodyweight).

• Features of hyperemesis gravidarum include dehydration, ketosis, weight loss (greater than 5%), postural hypotension, tachycardia and even collapse (as a result of dehydration and electrolyte imbalance).

Investigations




• Investigations are only required where there is concern regarding risk to the health of the mother or fetus. o Urinalysis may show ketonuria o Serum electrolytes, urea, and creatinine may be abnormal o Liver function tests may be abnormal o Thyroid function tests may reveal a high free thyroxine (T4) level (hyperthyroxinaemia)

or a low thyroid-stimulating hormone (TSH) level, or both, in up to 50% of women with hyperemesis gravidarum [Kuscu and Koyuncu, 2002]. High free tri-iodothyronine (T3) is much less common.

• Multiple pregnancy and hydatidiform mole should be excluded when hyperemesis gravidarum is diagnosed [Philip, 2003].

What other causes of nausea and vomiting in pregnancy are there? • Other causes should be considered if nausea and vomiting occurs for the first time after

9 weeks of gestation or if fever and abdominal pain (other than from retching) are present. These include: o Gastrointestinal (e.g. infection, appendicitis, gastritis, cholecystitis, peptic ulceration,

hepatitis, pancreatitis) o Genito-urinary (e.g. urinary tract infection, uraemia, ovarian torsion, kidney stones,

degenerating uterine leiomyoma) o Ear, nose and throat (e.g. labyrinthitis, Meniere's disease, motion sickness) o Metabolic (e.g. hypercalcaemia, Addison's disease, porphyria, diabetic ketoacidosis) o Psychological (e.g. eating disorders) o Neurological (e.g. vestibular lesions, migraines, tumours of the central nervous system) o Pregnancy-related (e.g. acute fatty liver of pregnancy, pre-eclampsia) o Drug toxicity or intolerance (e.g. morphine, digoxin, iron)

• In women with hyperemesis gravidarum and hyperthyroxinaemia: o If symptoms are severe or persist into the second trimester, a diagnosis of Graves'

disease should be considered [DTB, 1995]. o Goitre is not found with nausea and vomiting in pregnancy and if present may indicate

primary thyroid disease.

[ACOG, 2004; Davis, 2004]

Complications and prognosis Complications • Most cases of nausea and vomiting in pregnancy are self-limiting, and settle without

complication as pregnancy progresses. • Sleep disturbances may lead to increased fatigue and irritability [Davis, 2004]. • Time off work is needed by 35% of working women, who spend a mean of 62 hours

away from their paid work as a result of the symptoms of nausea and vomiting [Gadsby et al, 1993].

• In more severe cases, hospitalization is required because dehydration, weight loss, electrolyte disturbance, and nutritional deficiency can occur. Parenteral nutrition may also be necessary if the woman continues to lose weight.

• Hyperemesis gravidarum may lead to serious complications, including: o Wernicke's encephalopathy (due to a deficiency of vitamin B1/thiamine) which may lead

to maternal death or permanent neurological disability o Central pontine myelinolysis (an uncommon condition associated with rapid correction

of severe hyponatremia) o Spontaneous oesophageal rupture o Transient hyperthyroxinaemia (elevated free thyroxine [T4] and suppressed thyroid-

stimulating hormone [TSH]) which may not be associated with any clinical manifestations

o Depression secondary to hyperemesis gravidarum, which may develop in up to 60% of women, with some women electing to terminate their pregnancy

[Kuscu and Koyuncu, 2002; ACOG, 2004; Davis, 2004]

Prognosis • The effects on the fetus depend on the severity of the maternal symptoms. Overall,

nausea and vomiting of pregnancy is associated with favourable pregnancy outcomes. o There is a decreased risk of miscarriage and a lower incidence of perinatal death, and

preterm birth [Weigel and Weigel, 1989].




o With severe symptoms (abnormal electrolytes and weight loss) there may be an increased risk of low birth weight [Nelson-Piercy, 1997].

o No difference in the incidence of congenital malformations [Depue et al, 1987] was found between infants born to pregnant women who vomited and to those who did not.

[ACOG, 2004; Davis, 2004]

• Hyperemesis gravidarum has not been associated with adverse pregnancy outcomes. o Studies have shown no increased incidence in adverse pregnancy outcomes in women

with hyperemesis gravidarum, compared with pregnant women without hyperemesis gravidarum.

o There is a higher incidence of low birth weight among infants born to women with hyperemesis gravidarum.

o Gestational age, preterm delivery, APGAR scores, perinatal mortality and fetal malformations did not differ.

[Tsang et al, 1996; Kuscu and Koyuncu, 2002; ACOG, 2004; Davis, 2004]

Management issues Overview of management

• Consider and rule out other causes of nausea and vomiting, both pregnancy-related and unrelated to pregnancy (see What other causes of nausea and vomiting in pregnancy are there?), even if the diagnosis of nausea and vomiting in pregnancy seems straightforward.

• Offer reassurance and support. • Suggest dietary and lifestyle changes that may alleviate symptoms. • Consider drug treatment or hospitalization if symptoms are persistent, severe, and prevent

daily activities.

What first-line measures should I recommend? • Reassure the woman that this is a normal part of pregnancy and that pregnancy outcomes

are generally better for women who suffer from nausea and vomiting in early pregnancy. • Support from family and friends is regarded as helpful. • Advise rest as tiredness can make nausea worse. • Advise drinking little and often rather than in large amounts, as this may help to prevent

vomiting. • Although there is no research-based evidence, it is common practice to recommend:

o Small, frequent meals high in carbohydrate and low in fat o Eating cold meals rather than hot meals, which may prevent any smell-related nausea,

as cold food does not seem to give off as much smell as hot food o Eating plain (or ginger) biscuits about 20 minutes before getting up o Glucose tablets to possibly help prevent blood sugar levels from dropping (low blood

sugar levels may cause nausea) o Avoiding any foods or smells that trigger symptoms o Avoiding drinking cold, tart, or sweet beverages o Avoiding caffeine and alcohol, to prevent dehydration

[NTIS, 1999a; SOGC, 2002; Davis, 2004]

What should I do if symptoms are severe despite first-line measures? • When symptoms are persistent, severe, and prevent daily activities, drug treatment should

be considered. • Women with raised urine ketone levels should be started on drug treatment.

[Broussard and Richter, 1998; Kuscu and Koyuncu, 2002]

Which drugs can be used to treat nausea and vomiting in pregnancy in primary care? No drug is licensed for the treatment of nausea and vomiting of pregnancy in the UK.

Antihistamine anti-emetics — promethazine and cyclizine • Promethazine and cyclizine are recommended first-line treatment. They have been

widely used in pregnancy, and have not been associated with an increased risk of congenital malformations in infants born to mothers exposed to these drugs during pregnancy [Mazzotta and Magee, 2000; Kallen, 2002].

• Promethazine is preferred as it is the most studied [NTIS, 2002].




o One systematic review demonstrated no increased risk of major malformations following the use of promethazine in pregnancy (n = 1006) [Magee et al, 2002]. The authors pooled the data for all phenothiazines (including promethazine) and showed no association between phenothiazine use and the risk of malformations (RR 1.00, 95% CI 0.84 to 1.18).

o Drug exposure during pregnancy was identified from the Swedish Birth Registry and included 678 women taking promethazine only and 309 women taking cyclizine only [Kallen, 2002]. The rate of congenital malformations for promethazine was 3.14% and for cyclizine it was 3.17%, which did not differ from that seen in the general population (3.16%).

Prochlorperazine • Prochlorperazine is regarded as a second-line treatment because there are fewer safety data

available compared with promethazine and cyclizine [NTIS, 1999a]. o One review demonstrated no increased risk of major malformations following the use of

prochlorperazine in pregnancy (n = 1018) [Magee et al, 2002]. The authors pooled the data for all phenothiazines (including prochlorperazine) and showed no association between phenothiazine use and the risk of malformations (RR = 1.00, 95% CI 0.84 to 1.18).

Metoclopramide • Metoclopramide is considered safe for use in pregnancy and is also recommended as a

second-line treatment for nausea and vomiting in pregnancy [NTIS, 1999a]. o No major difference in the risk of congenital malformations (OR = 1.11, 95% CI

0.6 to 2.1) was found in a retrospective study of 309 women taking metoclopramide during pregnancy [Sorensen et al, 2000]. The incidences of low birth weight infants (OR = 1.79, 95% CI 0.8 to 3.9) or preterm delivery (OR = 1.02, 95% CI 0.6 to 1.7) were not significantly different.

o Two prospective studies, one including 126 women and the second including 175 women, showed no increase in malformation rate in infants born to women taking metoclopramide during the first trimester of pregnancy [Berkovitch et al, 2000; Berkovitch et al, 2002]. Both studies were carried out by the same authors and the women were recruited via teratology information services, and their pregnancies followed up prospectively. No information regarding the effectiveness of metoclopramide was reported.

Domperidone • Domperidone is not recommended to treat nausea and vomiting of pregnancy as there

are no published observational or trial data of its use in pregnancy [Magee et al, 2002].

When should I refer? • Women with hyperemesis gravidarum should be referred for parenteral fluid and

electrolyte replacement, together with vitamin supplementation. Nutritional support (enteral or parenteral) is needed in women who have intractable symptoms and weight loss despite appropriate therapy.

• Women with raised urine ketone levels, despite drug treatment, should be referred to secondary care.

Are vitamins an effective treatment? Multivitamins • Multivitamins before and during pregnancy are not recommended. • Although multivitamins have been successful in alleviating symptoms in some women, it is

difficult to know which ingredient is responsible and there is little good quality evidence of their effectiveness and safety during pregnancy.

• Taking multivitamins around the time of conception and during pregnancy may reduce the incidence or severity, or both of symptoms of nausea and vomiting in pregnancy. o A randomized placebo-controlled trial of 1000 women investigated the effect of

multivitamin supplementation on nausea and vomiting in pregnancy [Czeizel et al, 1992]. Women taking a multivitamin and mineral supplement (Ro 15-9473, ELEVIT prenatal®) for at least 1 month before conception and during the first trimester of pregnancy, showed a lower incidence in nausea and vomiting of severity that would prompt medical advice or treatment.

o A prospective observational study found that women taking multivitamins at the time of conception and during pregnancy were less likely to have episodes of vomiting (40%) than those who did not take multivitamins (59%) [Emelianova et al, 2001].

Pyridoxine




• Pyridoxine is not routinely recommended. • Although pyridoxine has been successful in alleviating symptoms in some women and is less

likely to cause adverse effects (e.g. drowsiness) than antihistamine anti-emetics [Jewell and Young, 2003], there is still uncertainty concerning effectiveness and the optimal dosage, which prevents a recommendation in this guidance for its use.

• A Cochrane review showed pyridoxine was effective at reducing nausea but there was no evidence of its effectiveness for vomiting [Jewell and Young, 2003]. The effect on nausea may be dose-related. Of the two studies included, the study investigating the higher dose showed greater effect. o One randomized controlled trial (RCT) showed a significant decrease in nausea in 169

women treated with 30 mg pyridoxine daily compared with those given placebo (p = 0.001). There was a non-significant trend in the number of vomiting episodes in the treated group (P = 0.06) [Vutyavanich et al, 1995].

o The other RCT reported improvement in nausea scores in 59 women with severe symptoms who were treated with 75 mg pyridoxine daily (p <0.01), but not in those with mild to moderate nausea. A significant reduction in vomiting for all patients (p <0.005) was also shown [Sahakian et al, 1991]. This study had a small sample size and evaluated only 3 days of treatment. Neither trial reported fetal outcome.

• No increase in malformation rate was found in a prospective observational study [Czeizel et al, 2004]. Information from a congenital malformation registry in Hungary did not find any difference in pyridoxine use between mothers of infants born with malformations compared with controls.

• Note: high-dose pyridoxine supplements taken over a prolonged time have been reported to cause peripheral neuropathy. Pharmacists have been advised by The Royal Pharmaceutical Society of Great Britain to consider how to advise patients wishing to purchase high-dose preparations (i.e. over 10 mg daily).

Are alternative and complementary therapies effective? Ginger • Although ginger root may be an effective treatment for nausea and vomiting of

pregnancy, it cannot be recommended in this guidance: o The active ingredient is unknown and the composition may vary widely. o There is insufficient good quality evidence of its effectiveness and safety.

• Ginger has been shown to reduce nausea and vomiting in pregnancy although the dose and form of ginger varied greatly across randomized controlled trials (RCTs): o A significant decrease in nausea and vomiting was reported in 27 women in hospital for

severe hyperemesis gravidarum who took 250 mg ginger compared with women who took 250 mg lactose [Fischer-Rasmussen et al, 1991].

o Ginger was effective for relieving the severity of mild and moderate nausea and vomiting in pregnancy [Vutyavanich et al, 2001].

o Ginger (350 mg) was therapeutically equivalent to pyridoxine (25 mg) in improving nausea, dry retching and vomiting in 291 women [Smith et al, 2004]. No complications of pregnancy or adverse effects were reported following the use of ginger in pregnancy.

o Some benefit was reported following use of 125 mg ginger extract in 120 women, compared with placebo (soya bean oil) [Willetts et al, 2003].

• The limited data on this issue indicate that ginger is safe for use in pregnancy: o Three RCTs (481 women in total) showed that the rate of birth defects in the children

of women taking ginger in pregnancy was similar to that in the general population [Vutyavanich et al, 2001; Willetts et al, 2003; Smith et al, 2004].

o One prospective observational study showed no increased incidence of adverse outcomes in 187 pregnant women using ginger compared with women not taking ginger during pregnancy [Portnoi et al, 2003]. There were no statistically significant differences between the two groups in terms of live births, infants with congenital malformations, spontaneous abortions, stillbirths, therapeutic abortions, birth weight or gestational age.

Acupuncture, acupressure, and acustimulation • A recent Cochrane review reported limited evidence of benefit of either acupuncture or

acupressure for treating nausea and vomiting in pregnancy [Jewell and Young, 2003]. • Acupressure may give relief to women and would seem to produce little risk of adverse

effect. Acupressure wristbands have the advantage of being inexpensive and available without a visit to the doctor or midwife.

• The acupuncture point most frequently used in traditional Chinese medicine for anti-emetic action is point 6 (P6) on the pericardium channel. This point is on the forearm, about three fingerbreadths proximal to the distal wrist crease, between the tendons of the flexor carpi radialis and palmaris longus muscles, about 1 cm deep.




• Acupressure involves the application of pressure at the P6 acupuncture point. It does not require needles, and can be applied using commercially available elastic bands holding a plastic disc that fit around the wrist.

• Acustimulation involves the application of a mild electrical current to the P6 point. • Acupuncture is not recommended for the treatment of nausea and vomiting of

pregnancy. o Two RCTs of 55 women [Knight et al, 2001] and 593 women [Smith et al, 2002] have

shown that acupuncture is no more effective than placebo (sham acupuncture) for treating nausea of pregnancy.

o However, these two studies showed that both acupuncture and sham acupuncture produced notable decreases in nausea, possibly as a result of the opportunity for women to discuss and have their symptoms recognized by professionals.

• Clinical trials on the use of acupressure have produced inconsistent findings. o A Cochrane systematic review showed that P6 acupressure has beneficial effects for

nausea and vomiting in pregnancy, and that this is comparable to that obtained by drugs [Jewell and Young, 2003].

o However, data from one of the largest RCTs was not in a form that could be included in the systematic review, and this trial showed no benefit from acupressure [Jewell and Young, 2003].

• Acustimulation is not recommended for the treatment of nausea and vomiting of pregnancy. o Two RCTs found nerve stimulation bands effective in reducing nausea and vomiting in

pregnancy [Evans et al, 1993; Rosen et al, 2003]. o An RCT of 187 women, showed acustimulation was effective at reducing nausea and

vomiting and promoting weight gain [Rosen et al, 2003]. Nerve stimulation therapy, provided by a small battery-powered device, was randomly allocated to 95 women, and 92 women used a sham device. The average improvement in total experience (frequency of nausea, vomiting and retching, and degree of distress) over the 21-day period was 6.5 (95% CL 5.3 to 7.7) in the nerve stimulation group and 4.7 (95% CI 3.7 to 5.6) in the placebo group.

o A small randomized placebo crossover study comparing an active sensory afferent stimulation (SAS) unit and an inactive placebo unit, showed symptom improvement in 20 women when the SAS unit was worn and in 10 when the placebo device was worn [Evans et al, 1993]. The placebo bands were identical in size and shape to the active bands but did not deliver an electrical stimulus.

Hypnosis, hypnotherapy, psychotherapy, and behaviour modification • No randomized trials investigating these treatments have been published. Two case series

carried out in 1946 and 1957 described successful treatment of severe forms of nausea and vomiting in pregnancy through hypnosis [Mazzotta and Magee, 2000].

Herbal remedies • Herbal remedies for nausea and vomiting in pregnancy, such as red raspberry and wild yam,

are available over the counter, but have not been studied formally. • Many herbal treatments have pharmacological effects on the body, and women should be

advised that there is no evidence of either efficacy or safety of these remedies.

Homeopathic treatment • No trials have been published regarding the use of homeopathy to treat nausea and

vomiting of pregnancy.

Medicines management How should drug treatment be prescribed? • In severe cases the intravenous or rectal route may be considered initially, where available,

and changed to the oral route when the symptoms begin to subside. • Promethazine is available as the hydrochloride or teoclate salt.

o The hydrochloride salt is offered as a regular night-time dose. It is available as 10 mg tablets, which can be titrated for optimal effect. Up to 25 mg can be taken as one dose, and this can be repeated in the morning if necessary.

o Promethazine teoclate is only available as a 25 mg tablet, which restricts dosing flexibility.

• Cyclizine is available as the hydrochloride salt at a dose of 50 mg taken up to three times daily.




• Prochlorperazine can be used in nausea and vomiting in pregnancy, for prevention (5–10 mg, two or three times daily) and treatment (20 mg immediately, followed, if necessary, by 10 mg 2 hours later).

• Metoclopramide is given at a dose of 10 mg three times daily.

[BNF 49, 2005]

What are the adverse effects of drug treatment? Promethazine and cyclizine • No increased risks of congenital abnormalities, above the background rate for the

population, have been reported when these drugs have been used in therapeutic doses [Seto et al, 1997].

• There is a risk of neonatal withdrawal symptoms; promethazine should therefore be stopped 2 weeks before delivery. However, the drug is very rarely required in late pregnancy.

• Drowsiness is a significant adverse effect with promethazine, although reported to a lesser extent with cyclizine, and it may diminish after a few days of treatment.

• Other adverse effects include headache, psychomotor impairment, and antimuscarinic effects such as urinary retention, dry mouth, blurred vision, and gastrointestinal disturbances.

Prochlorperazine • No increased risk of congenital abnormalities above the background rate for the

population has been reported when prochlorperazine has been used in therapeutic doses [NTIS, 1999b].

• There is a risk of neonatal withdrawal symptoms following chronic use of prochlorperazine, especially in the third trimester [NTIS, 1999b].

• Extrapyramidal symptoms are the most significant adverse effects reported with prochlorperazine use, although these are particularly reported with depot preparations.

• Drowsiness and antimuscarinic symptoms (such as dry mouth, constipation, difficulty with micturition, and blurred vision) are also reported.

Metoclopramide • No increased risk of congenital abnormalities following first-trimester exposure to

metoclopramide was found, compared with controls [Berkovitch et al, 2002]. • Extrapyramidal symptoms (particularly in young women), hyperprolactinaemia, and

occasionally tardive dyskinesia on prolonged administration have been reported. • Drowsiness, restlessness, diarrhoea, depression, neuroleptic malignant syndrome, rashes,

pruritus, and oedema have also been reported.

Domperidone • Adverse effects include extrapyramidal symptoms and rashes.

[NTIS, 1999a; Manx Pharma, 2001; Kallen, 2002; Diav-Citrin et al, 2003; Jewell and Young, 2003; BNF 49, 2005]

References NHS staff in England can link, free of charge, from references to the full text journal articles by clicking on [NHS Athens Full-text]. You will need an NHS Athens password to access these resources. Click here for Athens registration.

All references with links to [Free Full-text] are freely available online to users in England and Wales. This includes the full text of Department of Health papers and Cochrane Library reviews.

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4 Berkovitch, M., Elbirt, D., Addis, A. et al. (2000) Fetal effects of metoclopramide therapy for nausea and vomiting of pregnancy. New England Journal of Medicine 343(6), 445-446. [NHS Athens Full-text]

5 Berkovitch, M., Mazzota, P., Greenberg, R. et al. (2002) Metoclopramide for nausea and vomiting of pregnancy: a prospective multicenter international study. American Journal of Perinatology 19(6), 311-316.




6 BNF 49 (2005) British National Formulary. 49th edn. London: British Medical Association and Royal Pharmaceutical Society of Great Britain.

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32 NTIS (1999c) Metoclopramide use in pregnancy. Newcastle upon Tyne: National Teratology Information Service, Regional Drug and Therapeutics Centre.

33 NTIS (2002) Promethazine exposure during pregnancy. Newcastle upon Tyne: National Teratology Information Service, Regional Drug and Therapeutics Centre.

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